In 1763, the Reverend Edmund Stone took the first step toward
the discovery of one of the most commonly used medicines when he
noted that the bark of the English willow was an effective
treatment for patients suffering from a fever. Stone explained
the effect of willow bark by noting that ". . . many natural
maladies carry their cures along with them, or their remedies lie
not far from their causes." Thus, he argued, the English
willow grows in the same moist regions where one was likely to
catch the fever treated with its bark.

It took 50 years before the active ingredient in willow bark
was isolated and named salicin, from the Latin name for
the willow (Salix alba). Another 50 years elapsed before
a large-scale synthesis for this compound was available. By that
time, the compound was known as salicylic acid because
saturated solutions in water are highly acidic (pH = 2.4).

By the end of the 19th century, salicylic acid was being used
to treat rheumatic fever, gout, and arthritis. Many patients
treated with this drug complained of chronic stomach irritation
because of its acidity and the large doses (6-8 g/d) required.
Because his father was one of these patients, Felix Hoffman
searched the chemical literature for a less acidic derivative of
salicylic acid. In 1898, Hoffman reported that the acetyl ester
of salicylic acid was simultaneously more effective and easier to
tolerate than the parent compound. He named this compound aspirin,
taking the prefix a- from the name of the acetyl group
and spirin from the German name of the parent compound spirsaure.

The existence of a drug that reduced both pain and fever
initiated a search for other compounds that could achieve the
same result. Although it was based on trial and error, this
search inevitably produced a variety of substances, such as those
in the figure below, that are analgesics, antipyretics, and/or
anti-inflammatory agents. Analgesics relieve pain without
decreasing sensibility or consciousness. Antipyretics reduce the
body temperature when it is elevated. Anti-inflammatory agents
counteract swelling or inflammation of the joints, skin, and
eyes.

Salicylic acid

Acetylsalicylic
acid
(Aspirin)

Acetaminophen
(Tylenol)

Ibuprofin
(Motrin, Advil)

Although the use of aspirin has been widespread since the 19th
century, the mechanism for its action was first described in 1971
[J. R. Vane, Nature, 231(25), 232-235
(1971)]. Vane noted that injury to tissue was often followed by
the release of a group of hormones known as the prostaglandins,
which have wide-spread physiological effects at very low
concentrations. The prostaglandins regulate blood pressure,
mediate the inflammatory response of the joints, induce the
process by which blood clots, regulate the sleep/wake cycle, and,
when appropriate, induce labor.

Vane suggested that aspirin and other nonsteroidal
anti-inflammatory drugs (or NSAID's) inhibit the enzyme that
starts the process by which prostaglandins such as PGE2
and PGF2 are synthesized from the 20-carbon
unsaturated fatty acid known as arachidonic acid shown in the
figure below. The steroidal anti-inflammatory drugs (such as
hydrocortisone) achieve a similar effect by inhibiting the enzyme
that releases arachidonic acid into the cell.

PGE2

PGF2a

Now that they are beginning to understand the mechanism by
which drugs operate, medicinal chemists can approach the design
of drugs by a rational process. A recent paper described progress
toward the design of a drug to treat the debilitating diseases
caused by protozoan parasites that afflict millions of people in
Latin America, Africa, and Asia [W. N. Hunter, et al., Journal
of Molecular Biology, 227, 1992,
322-333]. The potential target for this drug is an enzyme
trypanothione reductase (TR) that
protects the parasite from oxidative damage from the immune
system of its mammalian host. Mammalian cells use a similar
enzyme, known as glutathione reductase (GR), to protect against
damage from oxidation reactions.

Hunter and coworkers found that the human GR enzyme has a
smaller, more positively charged active site than the TR enzyme
in the parasite. The structural information in this study can now
be used to rationally modify a substrate of these enzymes until
it possesses the following characteristics.

The substrate must be too large to bind to the GR enzyme
in humans.

The substrate must have a high affinity for binding to
the TR enzyme in the parasite.

The substrate must inhibit the activity of the TR enzyme,
thereby allowing the immune system of the mammalian host
to attack and eventually destroy the parasite.